Carfilzomib and Dexamethasone (CarDex)

Transcription

1 Carfilzomib and Dexamethasone (CarDex) Indication Relapsed multiple myeloma for patients who have had only one previous line of therapy (that did not include bortezomib). (NICE TA457) ICD-10 codes Codes with a pre-fix C90 Regimen details Cycle 1 Day Drug Dose Route 1 and 2 Carfilzomib 20 mg/m 2 (maximum 44mg) IV infusion 8 and 9, 15 and 16 Carfilzomib 56 mg/m 2 (maximum 123mg) IV infusion 1 and 2, 8 and 9, 15 and 16, 22 and 23 Dexamethasone* 20mg OM PO/IV Cycle 2 onwards Day Drug Dose Route 1 and 2, 8 and 9, 15 and 16 Carfilzomib 56 mg/m 2 (maximum 123mg) IV infusion 1 and 2, 8 and 9, 15 and 16, 22 and 23 Dexamethasone* 20mg OM PO/IV * Dexamethasone should be administered 30 minutes to 4 hours before carfilzomib. Cycle frequency 28 days Number of cycles Until disease progression or unacceptable toxicity. Consider a once weekly dosing schedule to help manage toxicity. Administration Pre and post hydration: Cycle 1, day 1: Oral hydration of 30mL/kg/day from 48 hours prior to commencing treatment is recommended. Pre- hydration with ml sodium chloride 0.9% IV is recommended with each dose during cycle 1. Consider additional post-hydration with mL sodium chloride 0.9%. For subsequent cycles consider pre- and posthydration if LDH or uric acid is elevated and / or patient is considered at risk for tumour lysis syndrome. Encourage oral fluid intake of 1L before and after each dose of carfilzomib to maintain adequate hydration. Carfilzomib is administered in mL glucose 5% by IV infusion over 30 minutes. Flush line with 5% glucose solution immediately before and after administration. Patients should be monitored for infusion related reactions, for 1 hour following each carfilzomib infusion during cycle 1 and following cycle 2 day 1 and thereafter if required. Version 1 Review date October 2019 Page 1 of 7

2 Dexamethasone is available as 500microgram and 2mg tablets. The dose should be taken in the morning, with or after food, 30 minutes to 4 hours before carfilzomib administration. Alternatively dexamethasone may be administered as an IV bolus. Pre-medication Dexamethasone as above. Emetogenicity This regimen has low emetogenic potential. Additional supportive medication H 2 antagonist or proton pump inhibitor. Allopurinol 300mg OD (100mg OD if CrCl< 20mL/min) for patients with a high tumour burden, for cycles 1 and 2. Bisphosphonates as per local policy. Laxatives if required. Antifungal, antiviral and PCP prophylaxis as per local policy. Thromboprophylaxis should be considered based on an individual benefit/risk assessment. Extravasation Carfilzomib is neutral (group 1). Investigations pre first cycle Investigation Validity period FBC and film Clotting screen U+Es (including creatinine) LFTs Glucose Blood pressure (lying and standing) Prior to cycle 1 Clinical assessment for cardiac disease. Consider ECG Prior to cycle 1 +/- echocardiogram in those with a history of cardiac disease or over 70 years of age. Serum electrophoresis (or alternative biological measure of response if M protein not measurable). Bone marrow aspirate and trephine. Investigations pre subsequent cycles Investigation Validity period FBC* 72 hours U+Es (including creatinine)* 72 hours LFTs 72 hours Blood pressure On day 1 Glucose As clinically indicated. Serum electrophoresis (or alternative biological measure of response if M protein not measurable). *Monitor FBC and renal function weekly before treatment in cycles 1 and 2 and subsequently if dose level adjustment for toxicity has been made. Version 1 Review date October 2019 Page 2 of 7

3 Standard limits for administration to go ahead If blood results not within range, authorisation to administer must be given by prescriber/ consultant. Investigation Limit Neutrophils 1.0 x 10 9 /L Platelets 75 x 10 9 /L Creatinine clearance 30mL/min (see below) Bilirubin < ULN ALT/AST < ULN Non-haematological toxicity Resolved to grade 1 Dose modifications Carfilzomib: Dose level Carfilzomib dose Full dose 56mg/m 2 First dose reduction 45mg/m 2 Second dose reduction 36mg/m 2 Third dose reduction 27mg/m 2 Continued toxicity Consider once weekly dosing; consider discontinuation Haematological toxicity Treatment on day 1 of each cycle should only be initiated if neutrophils 1.0 x 10 9 /L and platelets 75 x 10 9 /L. If cytopenia is considered to be disease related, treatment may be given at consultant discretion. For subsequent doses within each cycle: Haematological toxicity Neutrophils < 0.5 x 10 9 /L Febrile neutropenia (Neutrophils < 0.5 x 10 9 /L and an oral temperature > 38.5 C or two consecutive readings of > 38.0 C for 2 hours) Platelet count < 10 x 10 9 /L or evidence of bleeding with thrombocytopenia Recommended action Withhold treatment. Once recovered to 0.5 x 10 9 /L, continue at same dose level For subsequent drops to < 0.5 x 10 9 /L, withhold treatment and consider recommencing with 1 dose level reduction. Withhold treatment. If neutrophil count returns to baseline grade and fever resolves, resume at the same dose level Withhold treatment. Once recovered to 10 x 10 9 /L and bleeding is controlled resume with same dose level For subsequent drops to < 10 x 10 9 /L, withhold treatment and consider recommencing with 1 dose level reduction. Version 1 Review date October 2019 Page 3 of 7

4 Renal impairment No starting dose adjustment for carfilzomib is recommended for baseline mild, moderate, or severe renal impairment or patients on chronic dialysis. However, in phase 3 clinical studies, the incidence of adverse events of acute renal failure was higher in patients with lower baseline creatinine clearance than that among patients with higher baseline creatinine clearance. Renal toxicity Serum creatinine equal to or greater than 2 baseline Creatinine clearance < 15 ml/min (or creatinine clearance decreases to 50% of baseline) or need for dialysis Recommended action Withhold carfilzomib and monitor renal function. Resume carfilzomib when renal function has recovered to within 25% of baseline. Consider resuming at 1 dose level reduction. For patients on dialysis receiving carfilzomib, the dose is to be administered after the dialysis procedure. Hepatic impairment The pharmacokinetics of carfilzomib has not been evaluated in patients with severe hepatic impairment. No starting dose adjustment is recommended in patients with mild or moderate hepatic impairment based on available pharmacokinetic data. However, higher incidence of hepatic function abnormalities, grade 3 adverse events and serious adverse events have been reported in patients with mild or moderate baseline hepatic impairment compared with patients with normal hepatic function. Other toxicities Hypertension: including hypertensive crisis and hypertensive emergency, have been observed. Some of these events have been fatal. All patients should be routinely evaluated for hypertension and treated as needed. Pulmonary Toxicity: including Acute Respiratory Distress Syndrome, acute respiratory failure, and acute diffuse infiltrative pulmonary disease: Withhold carfilzomib and evaluate promptly Dyspnoea: For severe or life threatening dyspnoea, withhold carfilzomib and evaluate. All other grade 3 or 4 non-haematological toxicities: Withhold carfilzomib until resolved or returned to baseline. Recommence with 1 dose level reduction. Dexamethasone: Suggested dexamethasone dose reductions if required: Dose level Dexamethasone dose Full dose 20mg OM Dose level -1 12mg OM Dose level -2 8mg OM Dexamethasone is usually discontinued following 2 dose reductions. Version 1 Review date October 2019 Page 4 of 7

5 Dexamethasone dose modifications: Toxicity Grade Dose Modification Dyspepsia Grade 1-2 Maintain dose and treat with H2 antagonist or PPI as per local policy. Reduce dose one level if symptoms persist. Grade 3 Withhold until symptoms return to baseline. Add H2 antagonist or PPI as per local policy and resume with one dose level reduction. Oedema Grade 3 Withhold until symptoms return to baseline. Use diuretics as needed and resume with one dose level reduction. Confusion or mood alteration Grade 2 Withhold until symptoms resolve. Muscle weakness Grade 2 Withhold until muscle weakness Grade 1. Hyperglycaemia Grade 3 Withhold until treated with insulin or oral hypoglycaemic agents as needed. Acute pancreatitis Other dexamethasone adverse events Discontinue dexamethasone. Grade 3 Withhold until resolved to Grade 2. Adverse effects - for full details consult product literature/ reference texts The incidence of adverse events (including cardiac failure) in clinical trials was higher for patients who were 75 years of age compared to patients who were < 75 years of age. Serious side effects Myelosuppression Cardiac disorders, QT prolongation. Acute respiratory distress syndrome (ARDS), interstitial lung disease. Pulmonary hypertension Hypertension, including hypertensive crisis and hypertensive emergency Posterior reversible encephalopathy syndrome (PRES) Acute renal failure Tumour lysis syndrome Infusion related reactions Venous thromboembolic events Thrombotic microangiopathy Haemorrhage Hepatic toxicity Frequently occurring side effects Dyspnoea. Evaluate dyspnoea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Myelosuppression Diarrhoea, constipation Pyrexia Nausea and vomiting Fatigue Peripheral neuropathy Version 1 Review date October 2019 Page 5 of 7

6 Headache Hypertension Arthralgia, muscle spasms Hypokalaemia Hypophosphatemia Other side effects Significant drug interactions for full details consult product literature/ reference texts Carfilzomib is primarily metabolised via peptidase and epoxide hydrolase activities, and as a result, the pharmacokinetic profile of carfilzomib is unlikely to be affected by concomitant administration of cytochrome P450 inhibitors and inducers. Carfilzomib is a P-glycoprotein (P-gp) substrate. Carfilzomib inhibits the efflux transport of digoxin, by 25%. Caution should be observed when carfilzomib is combined with substrates of P-gp (e.g. digoxin, colchicine). Additional comments Contraception Female patients of child bearing potential (and/or their partners) must use effective contraception measures during and for one month following treatment. Male patients must use effective contraception measures during and for 3 months following treatment if their partner is pregnant or of childbearing potential and not using effective contraception. Sodium content Carfilzomib contains 0.3 mmols (7 mg) of sodium per ml of reconstituted solution. This should be taken into consideration for patients on a controlled sodium diet. References Summary of Product Characteristics: Cafilzomib (Amgen Ltd) accessed 18 July 2017 via National Institute for Clinical Excellence. Technology Appraisal Guidance NICE TA457. Accessed 18 July 2017 via Dimpopoulos M. et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. The Lancet Oncology, Volume 17, Issue 1, Amgen Data on File: ENDEAVOR Clinical Study Report, pages Written/reviewed by: Dr A Whiteway (Consultant Haematologist, North Bristol NHS Trust) Checked by: Sarah Murdoch (Senior Oncology/Haematology Pharmacist, SW Clinical Network) Authorised by: Dr J Braybrooke (Consultant Oncologist, SW Clinical Network) Date: October 2017 Version 1 Review date October 2019 Page 6 of 7

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